This is a continuation of a research program that has been supported by NIMH and NIDA for a number of years. The purpose of this research is to delineate some of the pharmacological characteristics of tolerance and dependence to the narcotic analgesics. The experiments outlined will continue work on the characteristics and properties of tolerance and dependence and explore several avenues of approach to this problem. We propose to continue an investigation of the factors involved in the appearance, maintenance and loss of tolerance and physical dependence as they relate to dose, dose intervals and the chemical structures of the narcotic analgesics administered. The study also proposes to further explore the interrelationship of tolerance and physical dependence with respect to onset, duration and disappearance. We shall carry out these studies using analgesic assays and temperature changes as measurements of tolerance and weight loss, and behavioral changes and temperature changes as indicators of physical dependence. As part of these studies we will expand the exploration of the feasibility of using one parameter of drug effect, namely temperature, as a measure of both tolerance and dependence. We will use the complex interrelationship of agonist and antagonist to further investigate the nature of the drug-receptor occupation and the nature of the initiation of the changes resulting in tolerance and dependence. Explorations of the prevention of tolerance and dependence by the concommitant administration to agonist and antagonist or by the prior administration of antagonist or by the subsequent administration of antagonist will be continued. Agents affecting protein synthesis and short-term memory will also be used to investigate the nature of this drug-receptor interaction more fully. The course of non-antagonist-precipitated withdrawal will be studied in both rats and mice using the temperature changes induced by the abrupt cessation of chronic narcotic administration.